Despite it being a relatively common complication and most common cause of death, relatively little is known about the biology underlying recurrent disease, and there have been relatively few studies, all retrospective, that have dealt primarily with subsequent clinical outcomes of patients whose disease has recurred following allogeneic hematopoietic stem cell transplantation (HSCT). Most importantly, treatment options are extremely limited for patients with who experience disease recurrence or progression following allogeneic HSCT. These options include the withdrawal of immune suppression and/or the administration of additional donor lymphocytes (a.k.a. donor lymphocyte infusion;DLI) in order to induce a graft-versus-tumor (GVT) effect, the use of conventional therapeutic treatments for the respective disease, or a second allogeneic HSCT. With the exception of chronic phase chronic myelogenous leukemia (CML), these treatments only benefit a minority of patients, the benefits are often transient, and the treatments are associated with a high degree of morbidity, particularly graft-versus-host disease (GVHD). In addition, many of these therapies are not applicable to patients in whom disease recurs while experiencing active GVHD. Despite this being a relatively common and life-threatening complication and the ineffectiveness and limited availabilities of therapies, only a very small minority of patients (estimated to be less than 5%) are treated on IRB-approved clinical trials. There are a number of reasons for this. First is the common practice among transplant physicians to attempt to induce a GVT effect through either withdrawal of immune suppression and/or DLI. However, as previously mentioned these maneuvers benefit only a minority of patients and result in GVHD in a majority of patients. Subsequently options are limited and prognosis is grave. Second, a significant portion of available phase I and II trials preclude patients who either have undergone prior allogeneic HSCT or have active GVHD. Third, given the historically poor outcomes of patients once they have either failed to respond or were deemed ineligible to receive, there continues to be a general sense of nihilism among transplant physicians, thus opting for palliative care rather then experimental therapy, which in itself is very limited. As stated in the NCI Center for Cancer Research (CCR) Strategic plan, the intramural program is capable of performing long-term, high-risk research that may be too complex or challenging for academia or private industry to take on. It is our commitment to studying relatively rare but devastating cancers, and cancers predominant in medically underserved populations. The scientific and clinical interests, expertise, and resources of the CCR are ideally suited to take on this devastating problem, considering that over 10,000 patients undergoing allogeneic HSCT annually for malignancy in the United States alone. It is our goal to develop a coordinated program for the study and treatment of patients with recurrent malignancies following allogeneic HSCT. This program is a natural extension of our interest in enhancing graft-versus-tumor effects and takes advantage of the research interests and resources for these diseases within the intramural NCI programs (e.g. POB), and the particular research interests and expertise within the ETIB. There are already several protocols in place or in development by both the ETIB and POB, which are specifically designed for the treatment of recurrent disease after allogeneic HSCT. To integrate these efforts, we have formed a working group, consisting of translational and clincial scientists, and have designed a specific natural history protocol to study relapse after allogeneic HSCT will play an important role in the program development. This protocol is intended for both the long-term study of patients and to in recruiting patients with who experience disease recurrence or progression following allogeneic HSCT. Once enrolled onto this protocol, patients will be readily accessible and aware of the various investigative options available to them for their recurrent malignancy. This study serves at least three important functions. First, there have been relatively few studies of natural history of patients once they developed recurrent disease, particularly for patients with lymphoid malignancies. By prospectively following this cohort of patients, we will be able to identify risk factors for both relapse and for subsequent response to therapy. Second, participation in this natural history trial may benefit patients in that it will allow them access to a center which had dedicated itself to addressing this important problem that is currently not present in even the largest transplant programs. Finally, it will assure a steady stream of patients with hematologic malignancies that will serve as a valuable educational resource for clinical fellows in pediatric and medical oncology. We will implement this protocol through a specific relapse clinic which will also be run in a multi-disciplinary manner. In addition, in November 2009 the NCI will be hosting an international workshop on the biology, prevention, and treatment of relapse after allogeneic HSCT. This workshop will bring together basic, translational and clinical scientists from around the world to to generate and discuss key research questions related to the problem of relapse after transplant.